Chronic obstructive pulmonary disease (“COPD”) is a disease state characterized by airflow limitation that is not fully reversible, and that is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gas. Global Initiative for Chronic Obstructive Lung Disease Workshop Report (2004) (“Gold Report”).
COPD is the fourth leading cause of chronic morbidity and mortality in the United States, Gold Report, and is the fifth leading cause of death in the world, Rabe, “Outcome measures in COPD,” Primary Care Respiratory J. 13:177-178 (2004); World Health Organization, World Health Report 2002.
In 1993, the 15.7 million cases of COPD in the United States were estimated to present an annual economic burden of $23.9 billion; in the United Kingdom, the direct cost of COPD in 1996 was approximately $1.4 billion, with indirect costs estimated at approximately $3.4 billion. Gold Report 2004. Worldwide, prevalence is increasing, and by 2020 COPD is projected to rank fifth in terms of worldwide disease burden.
Currently, treatment of COPD is largely palliative; none of the existing approaches clearly halts progression of the disease.
Typically, the clinical manifestations of COPD are associated with histopathologic evidence of emphysema, defined as destruction of the alveoli. Cigarette smoke-induced emphysema is a principal contributor to the pathogenesis of COPD.
Smoke-induced emphysema is presumed to result, at least in part, from an imbalance between protease and antiprotease activity in the lungs.
Individuals with hereditary deficiency of alpha 1-antitrypsin (AAT), a major inhibitor of neutrophil elastase, are known to develop panacinar emphysema, even in the absence of smoke exposure. Cigarette smoke is known to oxidatively inactivate alpha 1-antitrypsin (AAT), and smoke exposure is known to cause an increase in the numbers of protease-secreting inflammatory cells, including neutrophils, in the lungs, causing an analogous protease-antiprotease imbalance in the lungs of individuals without hereditary AAT deficiency. Reviewed in Churg et al., Curr. Opin. Pulm. Med. 11:153-159 (2005).
Mice lacking neutrophil elastase (NE) are approximately 60% protected against smoke-induced emphysema, Shapiro, Clin. Chest Med. 21:621-632 (2000). Conversely, peritoneal administration of AAT to NE+ mice provides partial protection from smoke-induced emphysema, reducing airspace size by 63% as compared with the smoke-exposed animals, with concomitant decrease in TNF-α. Churg et al., Am. J. Respir. Crit. Care Med. 168:199-207 (2003).
These, and similar results, have led over the years to periodic suggestions that smoke-induced emphysema and COPD (of any etiology) be treated by AAT supplementation. U.S. Pat. No. 5,093,316, for example, describes and claims a method for treating the symptoms of pulmonary diseases, including COPD, by administering an effective amount of microcrystalline alpha 1-antitrypsin by inhalation. U.S. Pat. No. 6,489,308 proposes to treat a variety of disorders, including COPD, by administration of AAT. U.S. Pat. No. 5,993,783 describes a formulation of AAT intended for dry powder delivery to the lungs of patients having certain types of emphysema.
Native human AAT derived from pooled human plasma is commercially available and approved for intravenous administration to patients having hereditary deficiency of alpha 1-antitrypsin. The presence of copurifying protein contaminants and the risk of transmitting infectious agents militates against more widespread use, however, and has motivated the development of recombinant AAT and engineered AAT muteins. Recombinant AAT has been produced, for example, in yeast, Rosenberg et al., Nature 312:77-80 (1984); U.S. Pat. No. 4,752,576; Travis et al., J. Biol. Chem. 260:4384-4389 (1985); and in plants, Terashima et al., Appl. Microbiol. Biotechnol. 52:516-23 (1999) and Huang et al., Biotechnol. Prog. 17:126-33 (2001).
One type of recombinant AAT produced in Saccharomyces cerevisiae, rAAT, has an amino acid sequence identical to human plasma AAT with the exception of an N-acetylmethionine residue at the amino terminus. Unlike native human AAT, rAAT is unglycosylated.
Although production of rAAT in yeast provides certain advantages in terms of yield, cost, and ease of purification, the unglycosylated yeast-derived rAAT is considerably less tolerant of heat than its natural glycosylated counterpart. Travis et al., J. Biol. Chem. 260:4384-4389 (1985). Unglycosylated rAAT also has a far shorter biological half life.
Despite the partial protection from smoke-induced emphysema afforded by intraperitoneal supplementation with glycosylated human AAT in mice, and despite the various suggestions that AAT be delivered by inhalation to patients suffering from or at risk for COPD, the ability to achieve protective levels of antiprotease by inhalation of an unglycosylated recombinant protein in the concurrent presence of oxidizing cigarette smoke cannot be predicted. Furthermore, native AAT is inactivated by matrix metalloproteases, which are often elevated in the lungs of smokers; the ability to achieve protective levels of antiprotease by inhalation of an unglycosylated recombinant AAT in the concurrent presence of matrix metalloproteases cannot be predicted. In particular, it cannot be predicted whether pulmonary administration can provide protective levels of antiprotease activity in the lung interstitium at risk for protease degradation in smokers.
There still exists a need for effective methods of treating smoking-induced emphysema and COPD. There exists, in particular, a continuing need for treatments that can halt or retard progression in airflow limitation in individuals having, or at risk for, smoke-induced emphysema and COPD. There exists a further need for therapeutic methods that do not rely upon administration of agents derived from human plasma.